Vitamin B6 Effects on One-Carbon Metabolism

维生素 B6 对一碳代谢的影响

基本信息

批准号：
7888662
负责人：
JESSE F. GREGORY
金额：
$ 71.05万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888662
关键词：
Age Amino Acids Biostatistical Methods Carbon Cardiovascular Diseases Catabolism Cell physiology Chronic Coenzymes Computer Simulation Contraceptive Usage Cystathionine Cysteine Data Evaluation Generations Gluconeogenesis Glucose Glutathione Glutathione Metabolism Pathway Glycine Glycine Hydroxymethyltransferase Goals Health Homocysteine Homocystine Human Intake Kinetics Label Link Metabolic Metabolic Control Metabolism Methionine Methionine Metabolism Pathway Methylation Nutritional status Oral Contraceptives Pathway interactions Pattern Plasma Play Population Process Production Protocols documentation Pyridoxal Phosphate Research Risk Role Serine Skeleton Stroke Sulfur Amino Acids Supplementation Testing Tracer Tryptophan Tryptophan Metabolism Pathway Vascular Diseases Venous Thrombosis Vitamin B 6 Deficiency Vitamin B6 Woman base cardiovascular disorder risk functional status glucose-cysteine glycine cleavage system in vivo insight mathematical model metabolomics methyl group nucleotide metabolism nutrition public health relevance pyridoxine reproductive response restoration simulation tool transmethylation

项目摘要

DESCRIPTION (provided by applicant): Adequate vitamin B6 status is important for health, whereas low B6 status is associated with increased risk of cardiovascular disease, venous thrombosis and stroke. The mechanisms responsible are unknown, but the risk largely is independent of plasma homocysteine concentration. Through its coenzyme form pyridoxal phosphate (PLP), B6 plays essential roles in the acquisition and processing of one-carbon (1C) units by the glycine cleavage system and serine hydroxymethyltransferase, inter conversion and catabolism of amino acids, control of homocysteine, and production of glucose and cysteine. Thus, B6 nutrition is linked many vital cellular processes such as the synthesis of nucleotides and glutathione, metabolism of most amino acids, including sulfur amino acids, methylation processes, and gluconeogenesis. Low B6 status potentially can interfere with many of these processes. A large segment of the population, women of reproductive age, has compromised B6 status associated with the use of oral contraceptives (OC). The proposed research will determine the metabolic consequences of chronically low B6 status and the effects of targeted B6-repletion in women using OC. The linkages between vitamin B6 nutrition, B6-dependent metabolism and human health constitute the overarching rationale for these studies. In three protocols, kinetic and metabolomic assessments will be conducted in OC users before and after supplementation with pyridoxine to allow a thorough functional evaluation of unsupplemented OC users and the metabolic restoration provided by supplementation. The Aim 1 protocol will employ labeled serine and methionine to assess the in vivo kinetics and functional status of 1C metabolism and related processes, and the linkage between 1C metabolism and gluconeogenesis. Aim 2 studies will use labeled glycine as the primary tracer to determine the rates of in vivo glycine metabolism, glycine-based generation of 1C units, and determine the rate of glutathione synthesis. The Aim 3 protocol will assess the functional status of the methionine cycle (remethylation, transmethylation and transsulfuration) using labeled methionine tracers. In Aim 4, the data from these protocols and concurrent metabolic profiling will be subjected to multivariate statistical analysis to determine the relationships among the various kinetic fluxes and metabolite patterns to gain insight into metabolic control relationships. Exploratory mathematical modeling and simulations (Aim 5) of 1C metabolism and related processes also will be conducted to gain further insight into the metabolic effects of chronic OC use and effects of supplementation. Overall, these studies will yield new understanding of the metabolic effects of chronically low vitamin B6 status associated with OC use and the restorative effects of appropriate vitamin B6 supplementation. These findings will yield important new insight into mechanisms responsible in part for elevated risk of vascular disease in a major segment of women of reproductive age. PUBLIC HEALTH RELEVANCE: Many women using oral contraceptives (OC) have chronically low vitamin B6 nutritional status, which may have little relation to vitamin B6 intake level. Chronic vitamin B6 deficiency is associated with increased risk of several forms of vascular disease including cardiovascular disease, venous thrombosis and stroke. These studies will expand our understanding of the functional impact of vitamin B6 inadequacy in OC users and will provide a metabolically validated supplementation strategy to alleviate low B6 status and promote health in OC users.

描述（由申请人提供）：充足的维生素 B6 状态对健康很重要，而维生素 B6 状态低则与心血管疾病、静脉血栓形成和中风的风险增加相关。其机制尚不清楚，但风险很大程度上与血浆同型半胱氨酸浓度无关。通过其辅酶形式磷酸吡哆醛 (PLP)，B6 在甘氨酸裂解系统和丝氨酸羟甲基转移酶获取和加工一碳 (1C) 单位、氨基酸的相互转化和分解代谢、同型半胱氨酸的控制和生产中发挥重要作用葡萄糖和半胱氨酸。因此，B6 营养与许多重要的细胞过程相关，例如核苷酸和谷胱甘肽的合成、大多数氨基酸（包括含硫氨基酸）的代谢、甲基化过程和糖异生。低 B6 状态可能会干扰其中许多过程。很大一部分人口，即育龄妇女，因使用口服避孕药 (OC) 而导致 B6 状态受损。拟议的研究将确定长期低 B6 状态的代谢后果以及使用 OC 的女性有针对性地补充 B6 的影响。维生素 B6 营养、B6 依赖性代谢与人类健康之间的联系构成了这些研究的总体原理。在三个方案中，将在补充吡哆醇之前和之后对 OC 使用者进行动力学和代谢组学评估，以便对未补充的 OC 使用者进行彻底的功能评估以及补充剂提供的代谢恢复。 Aim 1 方案将采用标记的丝氨酸和蛋氨酸来评估 1C 代谢和相关过程的体内动力学和功能状态，以及 1C 代谢和糖异生之间的联系。目标 2 研究将使用标记的甘氨酸作为主要示踪剂来确定体内甘氨酸代谢率、基于甘氨酸的 1C 单位生成率，并确定谷胱甘肽合成率。 Aim 3 方案将使用标记的蛋氨酸示踪剂评估蛋氨酸循环的功能状态（再甲基化、转甲基化和转硫作用）。在目标 4 中，来自这些方案和并发代谢分析的数据将接受多变量统计分析，以确定各种动力学通量和代谢物模式之间的关系，从而深入了解代谢控制关系。还将对 1C 代谢和相关过程进行探索性数学建模和模拟（目标 5），以进一步了解长期使用 OC 的代谢影响和补充剂的影响。总体而言，这些研究将对与 OC 使用相关的长期低维生素 B6 状态的代谢影响以及适当补充维生素 B6 的恢复作用产生新的认识。这些发现将对大部分育龄妇女血管疾病风险升高的部分机制产生重要的新见解。公共健康相关性：许多使用口服避孕药 (OC) 的女性长期维生素 B6 营养状况较低，这可能与维生素 B6 摄入水平关系不大。慢性维生素 B6 缺乏会增加多种血管疾病的风险，包括心血管疾病、静脉血栓形成和中风。这些研究将加深我们对 OC 使用者维生素 B6 不足的功能影响的理解，并将提供经过代谢验证的补充策略，以缓解 OC 使用者维生素 B6 水平较低的状况并促进健康。